Structure-activity relationships among benextramine-related tetraamine disulfides. Chain length effect on alpha-adrenoreceptor blocking activity.

Several N'-substituted N,N''-(dithiodi-2,1-ethanediyl)bis(1, omega-alkanediamines) were prepared and evaluated for their blocking activity on alpha-adrenoreceptors in the isolated rat vas deferens and human blood platelets. The results were compared with those obtained for benextramine (N,N''-(dithiodi-2,1-ethanediyl)bis[N'-[(2-methoxyphenyl)-methyl]- 1 ,6- hexanediamine], 10). Bendotramine (N,N''-(dithiodi-2,1-ethanediyl)bis[N'-[(2-methoxyphenyl)- methyl]-1,12-dodecanediamine], 16) proved to be as active as 10 on alpha 1-adrenoreceptors, showing that optimum activity is associated with two carbon chain lengths separating inner from outer nitrogens of tetraamine disulfides. On the other hand, 16 had no activity up to 20 microM at alpha 2-adrenoreceptors. The optimum activity at this receptor subtype was associated with a six to eight carbon chain (10-12). Furthermore, 10 proved to be more selective toward alpha 2-adrenoreceptors whereas 16 was a selective alpha 1-antagonist. The tetraamine disulfides were shown also to be potent inhibitors of human platelet aggregation induced by ADP or epinephrine. The potency increased with the carbon chain length. However, the results on platelets did not parallel those found in the rat vas deferens, indicating that differences exist between the alpha-adrenoreceptor subtypes investigated. In conclusion, 10 may be a useful tool in characterizing alpha 2-adrenoreceptors whereas 16 might help in investigating alpha 1-adrenoreceptors.